The first part of this proposal studies a widely-used animal model of depression. In this model, rats are exposed to uncontrollable shock (US), which produces behavioral changes that resemble human depression with respect to etiology, symptomatology, and responsiveness to antidepressant treatment. We hypothesized that depression of active behavior following exposure to US is mediated by a large fall in the concentration of norepinephrine (NE) in the locus coeruleus (LC) region of the brain, resulting in decreased availability of NE for release in the LC and, consequently, an understimulation of alpha-2 receptors that normally respond to this transmitter. Since LC alpha-2 receptors inhibit the firing of LC neurons, extracellular recordings from LC neurons in behaviorally depressed rats should reveal increased neuronal activity. The first aim of the proposal is to determine if exposure to US produces electrophysiological changes in the activity of LC neurons. To accomplish this, single unit recordings of LC neurons will be obtained, and the effects of US will be assessed on 1) spontaneous activity of LC neurons, and 2) the responsiveness of LC neurons to activating stimuli. The latter measure is particularly important because we have recently found tht responsiveness of LC neurons to stimulation is a more sensitive index of adrenergic inhibition of the LC than is spontaneous activity. The second part of the proposal will ascertain if other receptors on LC cells in addition to alpha-2 receptors also regulate the responsiveness of LC neurons to activating stimuli. Recent data from our laboratory indicates that not all inhibitory receptors on LC cells alter LC responsiveness. We propose to examine the effects of a number of pharmacological agents on the responsiveness of LC neurons. These results will determine if alpha-2 adrenergic receptors are unique in their ability to modulate LC responsiveness or whether other receptors on LC cells modulate the LC in a similar fashion. The third part of this proposal will determine whether as-yet- untested substances affect LC activity. We will determine if soluble products of the immune system, interleukins (IL-1, IL-2, IL-3), affect responsiveness of LC cells and/or spontaneous activity of LC cells. In addition, to test whether changes in LC activity can result from endogenously-released immune products, we will determine if ongoing immune reactions alter LC activity. This part of the proposal is directed toward the general question of how the immune system communicates with the brain.